Abstract Theentericnervoussystem(ENS)isacomplexnetworkofneuronsandgliathatdrivegastrointestinal (GI) functions. The ENS accomplishes a remarkable variety of roles independent of the CNS and is therefore referred to as ?the second brain?. In addition to regulating GI activities such as peristalsis, secretionofdigestiveenzymesandabsorptionofnutrients,theENSisalsoproposedasthe?gateway? between the external elements (e.g. environmental toxins, the gut microbiome and diet metabolites) and the brain. Recent studies have demonstrated that ENS in involved in neurological disorders includingParkinson?sdiseaseandAlzheimerdiseaseandtheENSpathologiescanbeginseveralyears beforetheonsetofclassicsymptomsrelatedtobraindamage.UnderstandingtheroleofENSinthese disorders could offer valuable insights into the initiation and progression of neurodegeneration and provide new therapeutic opportunities. Additionally, there is currently a high demand for developing accurateearly-stagediagnosticstrategiesforneurodegenerativeconditions,giventhegreatextentof neuronallossatthetimeofclinicaldiagnosisandtherestrictedrepaircapacityofneurons. Despite its high level of significance and clinical relevance, the contribution of the ENS to neurodegenerative disorders has remained elusive. This is largely attributed to the lack of an experimental framework to enable the systematic dissection of various contributing factors. In recent years, directed differentiation of human pluripotent stem cell technology has provided an excellent opportunitytodevelopplatformsformechanisticunderstandingofphysiology,andpathophysiologyin human cell-based models. In a study recently published at Nature (Fattahi et. al., 2016), we have succeeded in the derivation of human ENS lineages from human Pluripotent Stem Cells (hPSCs). AccesstothesecellsenablestheinvestigationofhumanENSdevelopmentandfunctionandprovides auniqueplatformfordiseasemodelinganddrugdiscovery.Here,buildingonourexcitingpreliminary data,weproposeaseriesofinnovativestrategiestoleveragehumanpluripotentstemcellstogaina better mechanistic understanding of the role of ENS in neurodegenerative diseases and identify candidatedrugtargetsandnewdiagnosticbiomarkers.